Breast cancer is a leading cause of mortality and morbidity among women. One of the priorities in breast cancer research is the discovery of new biochemical markers which can be used for diagnosis, prognosis and monitoring of breast cancer. The prognostic usefulness of these markers depends on the ability of the marker to distinguish between patients with breast cancer who require aggressive therapeutic treatment and patients who should be monitored. Because breast cancer is one of a few cancers that is dependent on steroid hormones and their receptors, analysis of estrogen receptor (ER) and progesterone receptor (PR) status is currently routinely performed as an aid in prognosis and selection of therapy. Other markers or indicators which are currently employed to diagnose and monitor breast cancer include: tumor size, age, aneuploidy, mitotic activity and Ki67 (Allred et al., J. Natl. Cancer Inst., 85, 200-206 (1993)).
Mutation of the p53 tumor suppressor gene is one of the most commonly known genetic defects in human cancer, including breast cancer. Mutations in p53 result in the expression of a mutant protein which can accumulate to high concentrations. Overexpression of p53 protein is an independent predictor of early disease recurrence (Allred et al., supra). The accumulation of p53 protein has also been found to be an independent marker of shortened survival (Thor et al., J. Nat'l Cancer Inst., 84, 845-855 (1992)). However, the majority of tumors that are estrogen and/or progesterone receptor-positive do not express mutant p53 protein.
Prostate cancer, like breast cancer, is dependent on steroid hormones. One of the hallmarks of prostate cancer is the appearance in serum, at elevated concentrations, of a 30-33 kD glycoprotein, prostate-specific antigen (PSA) (Oesterling, J. Urol., 145, 907-923 (1991)). PSA is a kallikrein-like serine protease that was thought to be exclusively produced by epithelial cells lining the acini and ducts of the prostate gland (Papsidero et al., J. Natl. Cancer Inst., 66, 37-41 (1981); Lilja, J. Clin. Invest., 76, 1899-1903 (1985); Watt et al., Proc. Natl. Acad. Sci. USA, 83, 3166-3170 (1986)). Because of its tissue specificity, PSA has been widely used as a marker to diagnose and monitor prostate cancer (Stamey et al., N. Engl. J. Med., 317, 909-916 (1987); Catalona et al., N. Engl. J. Med., 324, 1156-1161 (1991)).
However, a number of studies have demonstrated the presence of PSA in non-prostate tissue. For example, Yu et al. (Breast Cancer Res. Treat., 32, 291-300 (1994)) reported that the steroid hormone receptor-positive breast carcinoma cell lines T47-D and MCF-7 can be stimulated by androgens, progestins, antiestrogens, mineralocorticoids and glucocorticoids to produce PSA. Diamandis et al. (Breast Cancer Res. Treat., 32, 301-310 (1994)) reported that 30% of female breast tumor cytosolic extracts contain PSA immunoreactivity. In addition, it is disclosed in Diamandis (WO 94/27152) that the presence of PSA in breast tumors is associated with tumors that express ER and/or PR. Thus, it has been speculated that PSA may be useful as a prognostic marker for breast cancer (Yu et al., Cancer Res., 55, 2104-2110 (1995); Diamandis (WO 94/27152)).
Nevertheless, it is unclear whether PSA is correlated with ER and/or PR receptor status or has prognostic significance. In an analysis of a subset of breast tumors for PR and ER status, Yu et al. (Clin. Biochem., 27, 75 (1994)) disclose that immunoreactive PSA was only associated with PR, and no relationship was found between immunoreactive PSA and ER. In contrast, a 1995 report by Yu et al. (Cancer Res., 55, 2104 (1995)) found that PSA and ER were independent, although collaborative, markers for the prognosis of breast cancer. The authors also report that the presence or absence of PSA had no additional prognostic significance in steroid receptor-positive patients.
There is, therefore, a need for an inexpensive and simple prognostic and/or diagnostic marker for breast cancer that can function independently of, or in combination with, current employed markers.